Abstract Improper placement of peripherally inserted central catheters (PICCs) is costly and has serious complications for critically-ill patients. More than one million PICCs are placed each year to provide IV therapies, where navigation through the venous system is typically performed blind, or without navigation guidance. As a result, 30-55% of PICC tips are not optimally placed on the first attempt and require repositioning, which has an average direct cost of $223 per patient and often necessitates the removal and reinsertion of the catheter line. Approximately 17% of these improperly positioned PICCs are placed into the right atrium, which is associated with a multitude of life-threatening complications. Further, 8% of malpositioned PICCs are improperly navigated through the venous system, which increases the risk of venous or arterial perforation, local venous thrombosis, and catheter dysfunction. Improper placement of a PICC line also often requires referral to an interventional radiologist for fluoroscopic-guided central line placement, which is expensive ($1,000). Not surprisingly, half of all PICCs are administered to patients over the age of 60, so safe and accurate PICC placement is critical for providing high-quality care to older Americans. Despite serious adverse events associated with blind placement, available guidance systems have not been widely adopted. The Teleflex ARROW G4 VPS and the Bard Sherlock 3CG are over 90% effective for placement of a catheter tip into the superior vena cava (SVC) or cavoatrial junction (CAJ). However, compared with standard, blind placement, these devices are 30-70% more expensive, require skilled staff, and have longer procedure times. Additionally, these guidance systems rely on the use of ECG, so they are contraindicated for patients with cardiac arrhythmias, a common condition in older adults. To address the need for accurate, safe, and cost-effective PICC placement in all patients, TheraNova has developed PICCOLO, a thermodilution-based navigation, or thermo-navigation, catheter system for real- time vascular access guidance. We have designed PICCOLO with the following key innovations: 1) Provides real-time hemodynamic data for identification of key vascular landmarks, 2) Expands the patient population indicated for PICC guidance, and 3) Provides a cost-effective and easy-to-use solution. In a proof-of-concept animal study (n=1 pig), we found that the unique thermo-navigation signatures of five anatomical locations could be distinguished with our PICCOLO prototype. In this Phase I proposal, we will: 1) Optimize the signal resolution of the PICCOLO prototype by evaluating saline infusion parameters over varying pulsatile venous flow conditions in a benchtop model (Specific Aim 1), and 2) Compare the thermo-navigation profiles for PICC tip placement in several key vascular locations as compared to the CAJ in six pigs (Specific Aim 2). The data obtained through this proposal will demonstrate the feasibility of thermo-navigation to provide accurate guidance for vascular access. These data will also support a Phase II submission, which will include preclinical and clinical studies to validate accurate PICC placement in all adults, including older adults with arrhythmias.